SHIP1 negatively regulates proliferation of osteoclast precursors via Akt-dependent alterations in D-type cyclins and p27

Ping Zhou, Hideki Kitaura, Steven L. Teitelbaum, Gerald Krystal, F. Patrick Ross, Sunao Takeshita

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Osteoclasts arise from macrophage progenitors in bone marrow (BMMs) as a consequence of signaling events elicited by M-CSF and receptor activator of NF-κB ligand, acting on their unique receptors, via c-Fms and receptor activator of NF-κB. Both receptors activate the PI3K and MAPK pathways, which promote cell proliferation and survival. SHIP1 is essential, for normal bone homeostasis, as mice lacking the protein exhibit osteoporosis resulting from increased numbers of hyper-resorptive osteoclasts. In this study, we show that BMMs from SHIP1 null mice respond to M-CSF, but not receptor activator of NF-κB ligand, by increasing Akt activation. In consequence, there are up-regulation of D-type cyclins, down-regulation of the cyclin-dependent kinase inhibitor p27, and, therefore, increased phosphorylation of the retinoblastoma protein and cell proliferation. Surprisingly, cell survival of wild-type and knockout BMMs is unaltered. Finally, osteoclastogenesis and periarticular bone erosions are markedly increased in SHIP1-/- mice with inflammatory arthritis, a condition characterized by increased M-CSF expression. The SHIP1/Akt pathway therefore suppresses bone loss in pathological states associated with an excess of the cytokine.

Original languageEnglish (US)
Pages (from-to)8777-8784
Number of pages8
JournalJournal of Immunology
Volume177
Issue number12
DOIs
StatePublished - Dec 15 2006
Externally publishedYes

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Cyclin D
Osteoclasts
Macrophage Colony-Stimulating Factor Receptors
Bone and Bones
Cell Survival
Cell Proliferation
Cyclin-Dependent Kinase Inhibitor p27
Ligands
Retinoblastoma Protein
Macrophage Colony-Stimulating Factor
Phosphatidylinositol 3-Kinases
Osteogenesis
Osteoporosis
Arthritis
Homeostasis
Up-Regulation
Down-Regulation
Bone Marrow
Macrophages
Phosphorylation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

SHIP1 negatively regulates proliferation of osteoclast precursors via Akt-dependent alterations in D-type cyclins and p27. / Zhou, Ping; Kitaura, Hideki; Teitelbaum, Steven L.; Krystal, Gerald; Ross, F. Patrick; Takeshita, Sunao.

In: Journal of Immunology, Vol. 177, No. 12, 15.12.2006, p. 8777-8784.

Research output: Contribution to journalArticle

Zhou, Ping ; Kitaura, Hideki ; Teitelbaum, Steven L. ; Krystal, Gerald ; Ross, F. Patrick ; Takeshita, Sunao. / SHIP1 negatively regulates proliferation of osteoclast precursors via Akt-dependent alterations in D-type cyclins and p27. In: Journal of Immunology. 2006 ; Vol. 177, No. 12. pp. 8777-8784.
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